TETRAHEDRONLETTERS

Tetrahedron Letters 41 (2000) 8631–8634Pergamon

Reductive cyclization of v-azido/nitrocarbonyl compoundsby samarium iodide: a facile preparation of DNA-binding

pyrrolo[2,1-c ][1,4]benzodiazepine and its dimers†

Ahmed Kamal,* E. Laxman and P. S. M. M. Reddy

Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India

Received 16 June 2000; revised 20 August 2000; accepted 7 September 2000

Abstract

An efficient synthesis of pyrrolo[2,1-c ][1,4]benzodiazepines via reductive cyclization of v-azido/nitrocar-bonyl compounds employing samarium iodide is described. This methodology has also been extended forthe preparation of DNA-crosslinking DC-81 dimers. © 2000 Elsevier Science Ltd. All rights reserved.

Keywords: reductive cyclization; pyrrolobenzodiazepines; DNA-binding; samarium iodide; DC-81 dimers.

DNA-binding molecules are presently attracting interest due to their involvement in carcino-genesis and their use as antitumor agents and probes of DNA structure.1 The pyrrolo[2,1-c ][1,4]benzodiazepine (PBD) family of DNA-binding antitumor antibiotics (anthramycin) hasbeen extensively studied as a potential source of antitumor agents and DNA probes.2,3 Thenaturally occurring PBDs have been isolated from various Streptomyces species. It has been wellestablished that they exert their biological activity through covalent binding to the exocyclic N2of guanine in the minor groove of DNA.4

* Corresponding author.† IICT communication no. 4568.

0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.PII: S0040 -4039 (00 )01524 -0

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Many molecules based on the PBD ring system have been synthesized to improve upon theirbiological profile. In this search C-7 or C-8 linked dimers of PBD have been synthesized whichare capable of sequence selective DNA-interstrand cross-linking.5,6 For example, DC-81 dimersof this type are highly cytotoxic and very efficient sequence selective cross-linking agents.7,8

Recently, new DNA-interstrand cross-linking, C-2 linked PBD dimers have also been synthe-sized.9 Furthermore, hybrid molecules containing the PBD ring system have been recentlyreported with interesting minor groove DNA-binding properties.10,11

In view of the importance of these molecules we have been interested in the structuralmodifications of naturally occurring PBDs to improve their DNA-binding potential andsequence selectivity. We have also been involved in the development of new synthetic strategiesfor the PBD ring system.12–15 In this endeavor, we wish to report a new approach of practicalsignificance based on a reductive cyclization strategy for the PBD ring system and its dimersemploying SmI2.

The precursors, N-(2-azido/nitro-benzoyl)pyrrolidine-2-carboxaldehydes (1) were prepared byliterature methods.16 These upon reductive cyclization with SmI2, afforded the desired PBDimines (2) in 70–72% yields.17 It has been observed that reduction of either the azido or the nitrogroup does not have much effect on the yields of the desired product (2), except for the reductivecyclization of azido compounds that takes place in 1.5 h when compared to nitro compoundswhich is completed in 2 h (Scheme 1).

Scheme 1. (i) SmI2, THF, rt, 1.5–2 h. (a) R=R1=H; (b) R=H, R1=CH3; (c) R=OH, R1=OCH3

This approach has also been extended to the synthesis of DC-81 dimers. The precursor,methyl-(2S)-(4-hydroxy-5-methoxy-2-nitrobenzoyl)pyrrolidine-2-carboxylate (3), was synthe-sized as described in the literature.18 This was alkylated using the dibromoalkanes (4) to obtainthe 4,4%-(alkane-a,v-diyldioxy)bis[methyl-(2S)-N-(5-methoxy-2-nitrobenzoyl)pyrrolidine-2-car-boxylates] (5).19 There upon reduction with DIBAL-H gave the nitroaldehydes (6), which onreductive cyclization with SmI2 afforded DSB-120 (7, n=3) and other DC-81 dimers in 18–20%overall yields20 (Scheme 2).

The significant feature of this method is that it addresses many of the difficulties encounteredby the literature procedures, particularly solubility aspects after the dimerization process.6,8 Inthe present method, the precursor 3 is synthesized in a facile manner and dimerized later, whichleads to an improvement in the yield and ease of work up. Furthermore, this process avoidscontamination by mercuric salts unlike the well-known ethanedithiol deprotective cyclizationapproach employing HgCl2.

In summary, we have developed a new azido as well as nitro reductive cyclization routeemploying SmI2 for the preparation of the PBD ring system, and extended this work to includedimers resulting not only in improved yields but also a facile synthetic sequence. This work willassist investigators in the preparation of similar biologically significant DNA-interactive dimers.

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Scheme 2. (i) K2CO3, acetone, reflux, 36–48 h, 80–90%; (ii) DIBAL-H (4 equiv.), CH2Cl2, −78°C, 45 min, 72–78%;(iii) SmI2, THF, 2 h, 55–63%

Acknowledgements

One of the authors (E.L.) is thankful to the CSIR, New Delhi, for the award of a SeniorResearch Fellowship.

References

1. Neidle, S.; Thurston, D. E. In New Target for Cancer Chemotherapy ; Kerr, D.; Workman, P., Eds. DNAsequences as targets for new anticancer drugs. CRC: Boca Raton, FL, 1994; pp. 159–175.

2. Thurston, D. E.; Puvvada, M. S.; Neidle, S. Eur. J. Cancer 1994, 30A, 567.3. Thurston, D. E. In Molecular Aspects of Anticancer Drug–DNA Interactions ; Neidle, S.; Waring, M. J., Eds.

Advances in the study of pyrrolo[2,1-c ][1,4]benzodiazepine antitumor antibiotics. Macmillan: Basingstoke, UK,1993; Vol. 1, pp. 54–87.

4. Remers, W. A. The Chemistry of Antitumour Antibiotics ; Wiley Interscience: New York, 1988; Vol. 2, pp. 28–92.5. Farmer, J. D.; Rudnicki Jr., S. M.; Suggs, J. W. Tetrahedron Lett. 1988, 29, 5105.6. Bose, D. S.; Thompson, A. S.; Ching, J. A.; Hartley, J. A.; Berardini, M. D.; Jenkins, T. C.; Neidle, S.; Hurley,

L. H.; Thurston, D. E. J. Am. Chem. Soc. 1992, 114, 4939.7. Jenkins, T. C.; Hurley, L. H.; Neidle, S.; Thurston, D. E. J. Med. Chem. 1994, 37, 4529.

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8. Thurston, D. E.; Bose, D. S.; Thompson, A. S.; Howard, P. W.; Leoni, A.; Croker, S. J.; Jenkins, T. C.; Neidle,S.; Hartley, J. A.; Hurley, L. H. J. Org. Chem. 1996, 61, 8141.

9. Reddy, B. S. P.; Damayanthi, Y.; Lown, J. W. Synlett 1999, 7, 1112.10. Baraldi, P. G.; Balboni, G.; Cacciari, B.; Guiotto, A.; Manfredini, S.; Romagnoli, R.; Spalluto, G.; Thurston, D.

E.; Howard, P. W.; Bianchi, N.; Rutigliano, C.; Mischiati, C.; Gambari, R. J. Med. Chem. 1999, 42, 5131.11. Damayanthi, Y.; Reddy, B. S. P.; Lown, J. W. J. Org. Chem. 1999, 64, 290.12. Kamal, A.; Rao, N. V. Tetrahedron Lett. 1995, 36, 4299.13. Kamal, A.; Damayanthi, Y.; Reddy, B. S. N.; Lakshminarayana, B.; Reddy, B. S. P. Chem. Commun. 1997, 1015.14. Kamal, A.; Rao, M. V.; Reddy, B. S. N. Khim. Getrotsikl. Soedin. Chem. (Chem. Heterocycl. Compd.) 1998, 12,

1588.15. Kamal, A.; Reddy, B. S. N.; Reddy, G. S. K. Synlett 1999, 8, 1251.16. Kamal, A.; Reddy, B. S. N.; Reddy, B. S. P. Bioorg. Med. Chem. Lett. 1997, 7, 1825.17. Preparation of compound 2: To a stirred 0.1 M solution of SmI2 in THF (12.5 ml, 2.5 equiv.) was added

dropwise a solution of 1 (122 mg, 0.5 mmol) in THF (5 ml) under a nitrogen atmosphere, at room temperatureand the stirring was continued for 1.5 h. After completion of the reaction, as indicated by TLC (ethyl acetate),the solvent was evaporated, the mixture was dissolved in CHCl3 and then it was washed with saturated K2CO3.The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified byflash column chromatography using ethyl acetate–hexane (9:1) to obtain the pure imine (2) in good yields.Spectral data of compound 2a: 1H NMR: (CDCl3) d 1.90–2.36 (m, 4H), 3.52–3.92 (m, 3H), 7.28–7.56 (m, 3H),7.78 (d, 1H, J=4.6 Hz), 8.05 (d, 1H, J=5.2 Hz); MS: m/z 200 (M+, 100) 171, 160, 144, 120, 103, 83, 70.

18. Kamal, A.; Reddy, B. S. P.; Reddy, B. S. N. Tetrahedron Lett. 1996, 37, 2281.19. Preparation of compound 5: To a stirred solution of 1,3-dibromopropane (202 mg, 1.0 mmol) in dry acetone (50

ml) was added anhydrous potassium carbonate (1.38 g, 10.0 mmol) and the monomer nitroester 3 (648 mg, 2.0mmol). The reaction mixture was then heated under reflux for 48 h. After completion of the reaction, as indicatedby TLC, using ethyl acetate–hexane as a solvent system, the potassium carbonate, was removed by filtration andthe acetone evaporated under vacuum. The reaction mixture was purified by column chromatography using ethylacetate–hexane (8:2) as eluent to afford pure dimer 5 in quantitative yields. Spectral data of compound 5: 1HNMR (CDCl3): 1.90–2.12 (m, 2H), 2.22–2.46 (m, 8H), 3.50–3.65 (m, 4H), 3.70 (s, 6H), 3.82 (s, 6H), 4.18–4.34 (t,4H), 4.50–4.82 (m, 2H), 6.80 (s, 2H), 7.32 (s, 2H); MS: m/z 689 (MH+).

20. Preparation of DC-81 dimer (7): The dimeric nitroaldehyde (6a, 125 mg, 0.2 mmol) in THF (5 ml) was addedslowly to a stirred 0.1 M solution of SmI2 in THF (10 ml, 5 equiv.) at room temperature under a nitrogenatmosphere. The reaction was continued for 2 h and after completion of the reaction, the THF was evaporatedunder reduced pressure. This was dissolved in chloroform and washed with saturated K2CO3. The organic layerwas dried over MgSO4 and evaporated under reduced pressure, then purified by flash chromatography usingCHCl3:MeOH (9.5:0.5) as eluent to give the pure DC-81 dimer 7a in 60% yield. Spectral data of compound 7a:1H NMR (CDCl3): d 2.01–2.17 (m, 2H), 2.27–2.44 (m, 8H), 3.50–3.86 (m, 6H), 3.92 (s, 6H), 4.24–4.34 (m, 4H),6.86 (s, 2H), 7.51 (s, 2H), 7.65 (d, 2H, J=4.4 Hz); FAB MS: m/z 533 (MH+).

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